ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942

Abstract

The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin-and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

CDK7 inhibitors as anticancer drugs

“…The emergence of resistance to cancer treatment, including targeted therapies, remains a major issue, and it is possible that even if CDK7 inhibitors prove a clinical success, resistance may develop in some patients. To gain understanding of potential resistance mechanisms, cell lines with acquired resistance to both ICEC0942 and THZ1 have been developed [142,143].…”

“…ATP-binding cassette transporters (ABC-transporters) are a well-characterised mechanism of multidrug resistance in cancer and, when upregulated, can mediate the ATP-dependent efflux of drugs that are substrates. Upregulation of ABCB1, also known as p-glycoprotein, mediates resistance to THZ1 in neuroblastoma and lung cancer [142] and resistance to both THZ1 and ICEC0942 in breast cancer cell lines [143]. Increased expression of another ABC-transporter, ABCG2, results in resistance to THZ1 [142], but not to ICEC0942 [143].…”

“…Upregulation of ABCB1, also known as p-glycoprotein, mediates resistance to THZ1 in neuroblastoma and lung cancer [142] and resistance to both THZ1 and ICEC0942 in breast cancer cell lines [143]. Increased expression of another ABC-transporter, ABCG2, results in resistance to THZ1 [142], but not to ICEC0942 [143]. With no clinical data available as yet, it remains to be seen whether ABC-transporter upregulation will arise in the context of CDK7 inhibitor resistance in patients.…”

Pleiotropic Roles of ABC Transporters in Breast Cancer

“…Additionally, CDK7 as a key modulator in both the regulation of transcription and the cell cycle has been a potentially valuable cancer drug target. ABCB1 was identified as a common mechanism of resistance to the CDK7 inhibitors, ICEC0942 and THZ1, in MCF7 breast cancer cells [ 69 ]. Moreover, ABCB1 was reported to limit the intracellular retention of the photosensitising agent benzoporphyrin derivative (BPD) in photodynamic therapy (PDT) in the MCF7 breast cancer cell line [ 70 ].…”

TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters

“…Hence, ABCG2 can confer resistance to diverse and commonly utilized chemotherapeutics such as etoposide, methotrexate, and doxorubicin (31). Moreover, a recent report has revealed that enforced overexpression of ABCG2 can induce resistance to THZ1 in HEK293 cells and in silico docking studies suggest that THZ1 can directly bind to ABCG2 (32). We confirmed that ABCG2 mRNA (Figure 3C) and protein (Figure 3D) were upregulated in both MDA-MB-231R and MDA-MB-468R cells compared to the CDK7i sensitive/parental cells.…”